The effect of tremor on disability assessment in chronic inflammatory demyelinating polyradiculoneuropathy.

Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is common, often unresponsive to treatment, and may contribute to disability. We aim to investigate whether tremor is associated with disability as measured in daily practice and clinical trials, independent of other impairments. We included 76 CIDP patients in this cross-sectional study. We assessed tremor with the Tremor Research Group essential tremor rating assessment scale (TETRAS) and the Fahn-Tolosa-Marin clinical rating scale (FTM). Disability was measured with the inflammatory Rasch-built overall disability scale (I-RODS) and the adjusted Inflammatory Neuropathy Cause and Treatment disability scale (INCAT-DS, categorized separately in arm score, or total score). Impairments including strength, sensory impairment, and fatigue were measured using specific impairment scales. We tested whether "the presence of a clinically relevant tremor" (based on TETRAS and FTM) or "tremor severity" (FTM part B sum score) was associated with disability scores (I-RODS, INCAT-DS total score, and INCAT-DS arm score), independent of the impairment scores, using multivariate regression. Both "the presence of a clinically relevant tremor" and "tremor severity" were significantly associated with disability measured by the INCAT-DS (arm score and total score), but not the I-RODS, independent of strength, sensory impairment, and fatigue. The explained variances were low. Clinically relevant tremor can (partly) explain disability in CIDP, as measured with the INCAT-DS, independent of muscle strength, sensory deficits, and fatigue. To assess disease activity in CIDP patients with tremor, both impairment and disability outcomes should be assessed, as disability is caused partly by tremor while the effect of immunotherapy on tremor seems limited.

B-cell and T-cell receptor repertoire in chronic inflammatory demyelinating polyneuropathy, a prospective cohort study.

The immunopathophysiological mechanisms underlying chronic inflammatory demyelinating polyneuropathy (CIDP) in an individual patient are largely unknown. Better understanding of these mechanisms may aid development of biomarkers and targeted therapies. Both B- and T-cell dominant mechanisms have been implicated. We therefore investigated whether B-cell and T-cell receptor (BCR/TCR) repertoires might function as immunological biomarkers in CIDP. In this prospective cohort study, we longitudinally sampled peripheral blood of CIDP patients in three different phases of CIDP: starting induction treatment (IT), starting withdrawal from IVIg maintenance treatment (MT), and patients in remission (R). BCR and TCR repertoires were analyzed using RNA based high throughput sequencing. In baseline samples, the number of total clones, the number of dominant BCR and TCR clones and their impact on the repertoire was similar for patients in the IT, MT, and remission groups compared with healthy controls. Baseline samples in the IT or MT did not predict treatment response or potential relapse at follow-up. Treatment responders in the IT group showed a potential IVIg-induced increase in the number of dominant BCR clones and their impact at follow-up (baseline1.0 [IQR 1.0-2.8] vs. 6 m 3.5 [0.3-6.8]; P < .05, Wilcoxon test). Although the BCR repertoire changed over time, the TCR repertoire remained robustly stable. We conclude that TCR and BCR repertoire distributions do not predict disease activity, treatment response or response to treatment withdrawal.

Combined intravenous immunoglobulin and methylprednisolone as induction treatment in chronic inflammatory demyelinating polyneuropathy (OPTIC protocol): a prospective pilot study.

BACKGROUND AND PURPOSE: We hypothesized that combining intravenous immunoglobulin (IVIg) and intravenous methylprednisolone (IVMP) leads to more frequent remission compared with IVIg alone while maintaining the fast efficacy of IVIg. In this uncontrolled pilot study, we evaluated remission, rate of improvement and safety in patients with chronic inflammatory demyelinating polyradiculoneuropathy receiving induction treatment with combined IVIg and IVMP. METHODS: Consecutive treatment-naive patients with chronic inflammatory demyelinating polyradiculoneuropathy were treated with IVIg infusions, consisting of a 2 g/kg loading dose and 1 g/kg maintenance treatment every 3 weeks, combined with 3-weekly 1-g IVMP infusions, for a total of 18 weeks. The cumulative steroid dose was 7 g. Primary outcome was remission at 1 year in patients who completed the treatment schedule. Remission was defined as improvement at 18 weeks without the need for further immune treatment between end of the treatment schedule and 1-year follow-up. Improvement was defined as a minimal clinically important difference on the Inflammatory Rasch-Built Overall Disability Scale and/or an increase of ≥8 kPa in grip strength between baseline and week 18. RESULTS: A total of 20 patients were included; 17 completed the treatment schedule. A total of 13 (76%) of these patients improved at 18 weeks after start of treatment and 10 (59%) patients were in remission at 1 year. Serious adverse events were found in four patients. CONCLUSIONS: Short-term combined induction treatment with IVIg and IVMP induced remission in almost 60% of patients who completed the treatment schedule. Combined induction therapy was generally well tolerated. A randomized controlled trial is currently running to confirm efficacy and safety of IVMP as add-on treatment to IVIg.

Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED.

Paritaprevir is an orally bioavailable, macrocyclic drug used for treating chronic Hepatitis C virus infection. Its structures had been elusive to the public until recently when one of the crystal forms was solved by MicroED. In this work, we report the MicroED structures of two distinct polymorphic crystal forms of paritaprevir from the same experiment. The different polymorphs show conformational changes in the macrocyclic core, as well as the cyclopropylsulfonamide and methylpyrazinamide substituents. Molecular docking shows that one of the conformations fits well into the active site pocket of the NS3/4A serine protease target, and can interact with the pocket and catalytic triad via hydrophobic interactions and hydrogen bonds. These results can provide further insight for optimization of the binding of acylsulfonamide inhibitors to the NS3/4A serine protease. In addition, this also demonstrate the opportunity of deriving different polymorphs and distinct macrocycle conformations from the same experiments using MicroED.

Clinical outcome of CIDP one year after start of treatment: a prospective cohort study.

OBJECTIVE: To assess clinical outcome in treatment-naive patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: We included adult treatment-naive patients participating in the prospective International CIDP Outcome Study (ICOS) that fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for CIDP. Patients were grouped based on initial treatment with (1) intravenous immunoglobulin (IVIg), (2) corticosteroid monotherapy or (3) IVIg and corticosteroids (combination treatment). Outcome measures included the inflammatory Rasch-built overall disability scale (I-RODS), grip strength, and Medical Research Council (MRC) sum score. Treatment response, treatment status, remissions (improved and untreated), treatment changes, and residual symptoms or deficits were assessed at 1 year. RESULTS: Forty patients were included of whom 18 (45%) initially received IVIg, 6 (15%) corticosteroids, and 16 (40%) combination treatment. Improvement on ≥ 1 of the outcome measures was seen in 31 (78%) patients. At 1 year, 19 (48%) patients were still treated and fourteen (36%) patients were in remission. Improvement was seen most frequently in patients started on IVIg (94%) and remission in those started on combination treatment (44%). Differences between groups did not reach statistical significance. Residual symptoms or deficits ranged from 25% for neuropathic pain to 96% for any sensory deficit. CONCLUSIONS: Improvement was seen in most patients. One year after the start of treatment, more than half of the patients were untreated and around one-third in remission. Residual symptoms and deficits were common regardless of treatment.

Longitudinal humoral response after SARS-CoV-2 vaccination in ocrelizumab treated MS patients: To wait and repopulate?

OBJECTIVE: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count. METHODS: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70. RESULTS: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL). CONCLUSIONS: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.

Long-term satisfaction after neurological second opinions and tertiary referrals.

BACKGROUND AND PURPOSE: The number of second opinions (SO) and tertiary referrals (TR) in neurology is increasing. Previously, we showed that a day-care admission for neurological SO's and TR's often results in a new diagnosis and/or treatment advice and increases patient satisfaction. However, long-term satisfaction for these consultations has never been studied. The main purpose of this study was to investigate long-term satisfaction in these groups of patients. METHODS: A 2-year follow-up study in 300 patients who had attended a day-care clinic for SO and TR. Long-term satisfaction was assessed with a questionnaire using four Visual Analogue Scale (VAS) satisfaction items (ranging 0-10). Patients were asked if they had sought further consultations for the same problem after they had consulted the day-care clinic. A model was constructed to assess predictors for seeking new consultations. RESULTS: Overall satisfaction decreased 2.4 (SD 2.4) points during follow-up to the same level as before the consultation. The decrease was similar in SO and TR patients. Twenty-eight per cent of the patients consulted other health-care workers. Greater satisfaction immediately after the consultation was the only predictor for not seeking additional consultations (OR 0.78, 95% CI 0.61-0.99 for every point increase on VAS). CONCLUSION: Despite a high rate of new diagnoses and advised treatments, long-term satisfaction decreased after 2 years to baseline levels. These results question the long-term efficacy of a day-care clinic to evaluate neurological second opinions and tertiary referrals.

Virus discovery in chronic inflammatory demyelinating polyneuropathy.

The events triggering and/or sustaining the auto-immune response underlying chronic inflammatory demyelinating polyneuropathy (CIDP) are unknown. Similar to Guillain-Barré syndrome (GBS), a viral infection might play a role in CIDP. In this study, an virus detection method (VIDISCA-next generation sequencing) capable of detecting known and unknown viruses, was used to analyze the virome in serum of 47 CIDP patients at different time points of the disease and, when available, in cerebrospinal fluid (CSF) samples (N: 17). Serum samples of GBS patients (N:24) and healthy controls (N:114) were used for comparisons. In 5/47 (10.6%; 95% CI: 4-23) CIDP samples, 10/24 (42%; 95% CI: 22-63) GBS samples and 32/114 (28.1%; 95% CI: 20-37) healthy controls samples, anelloviruses were detected, generally regarded as a non-pathogenic species. Parvovirus B19 and GB virus C were found in two CIDP samples (4%). Parvovirus B19, HIV-1 and GB virus C were found in three GBS samples (13%). In 2/17 CIDP CSF samples, an anellovirus and polyomavirus were detected, probably due to contamination during lumbar puncture. No sequences of other viruses were detected in serum or CSF. A (persistent) viral infection sustaining the auto-immune response in CIDP seems therefore unlikely.

Second opinions and tertiary referrals in neurology: a prospective observational study.

BACKGROUND AND OBJECTIVE: The number of neurological second opinions (SO) and tertiary referrals (TR) is increasing. The main purpose of this study was to assess whether a day-care admission made a meaningful contribution to standard neurological outpatient care, for a wide range of second opinions and tertiary referrals. METHODS: All new patients attending an academic neurological day-care clinic in a 6-month period were investigated. Before admission, all previous medical correspondence and ancillary investigations were reviewed. On the day of admission, extensive time was available for clinical evaluation and additional ancillary investigations and an attempt was made to come to a final diagnosis. Demographic characteristics, duration of symptoms, patient satisfaction, new diagnoses and treatment consequences were studied. RESULTS: 300 patients (183 SO and 117 TR) were evaluated. In total 103 patients (35 %) received a new diagnosis (26 % SO vs. 48 % TR, p < 0.001) and 69 (67 %) of these had therapeutic implications. A new treatment advice was given to a total of 149 patients (50 %), which was similar in both groups (48 % vs. 53 %). Second opinions were considered medically less relevant than tertiary referrals (39 % vs. 64 %, p < 0.001). The number of new diagnoses differed largely between various diagnosis categories. Especially somatoform disorders and radicular syndromes were often newly diagnosed. CONCLUSION: A high number of second opinion and tertiary referral patients benefits from a day-care admission in a neurological outpatient clinic. Careful selection for referral of patients who will benefit from daycare admission may even enlarge the diagnostic and therapeutic yield.

Corticosteroids in chronic inflammatory demyelinating polyneuropathy : A retrospective, multicentre study, comparing efficacy and safety of daily prednisolone, pulsed dexamethasone, and pulsed intravenous methylprednisolone.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) can be treated with corticosteroids or intravenous immunoglobulins. Various corticosteroid regimens are currently used in CIDP, but it is unknown whether they are equally efficacious. In this retrospective study, we compared efficacy and safety of three corticosteroid regimens in CIDP patients. METHODS: We included treatment naïve patients that fulfilled the EFNS/PNS criteria for CIDP. Patients were treated with corticosteroids according to the local protocol of three CIDP expertise centres. Corticosteroid regimens consisted of daily oral prednisolone, pulsed oral dexamethasone, or pulsed intravenous methylprednisolone. Outcomes were number of responders to treatment, remission rate of treatment responders, overall probability of 5-year remission, and the occurrence of adverse events. RESULTS: A total of 125 patients were included. Sixty-seven (54%) patients received daily prednisone or prednisolone, 37 (30%) pulsed dexamethasone, and 21 (17%) pulsed intravenous methylprednisolone. Overall, 60% (95% CI 51-69%) responded to corticosteroids, with no significant difference between the three treatment regimens (p = 0.56). From the 75 responders, 61% (95% CI 50-73%) remained in remission, during a median follow-up of 55 months (range 1-197 months). The probability of responders reaching 5-year remission was 55% (95% Cl 44-70%), with no difference between the three groups. Adverse events leading to a change in treatment occurred in ten patients (8%). Two patients had a serious adverse event. CONCLUSION: Corticosteroids lead to improvement in 60% of patients and to remission in 61% of treatment responders. There were no differences between treatment modalities in terms of efficacy and safety.

Examination of cardiovascular and peripheral autonomic function in the ICU: a pilot study.

UNLABELLED: Critical illness may affect the autonomic nervous system. Decreased cardiovascular autonomic function measured by heart rate variability (HRV) has been reported in critically ill patients but limited information exists about other autonomic functions. The cold face test (CFT) and skin wrinkle test (SWT) have never been investigated in critically ill patients. Feasibility and safety of the CFT and SWT were investigated in critically ill patients. EXCLUSION CRITERIA: polyneuropathy, autonomic neuropathy, admission after stroke, spinal cord injury or cardiac arrest. For the CFT, a cold pack was applied to the forehead to measure the maximal increase in RR interval. The simulated SWT was used and wrinkling was assessed on a five-point scale. HRV was investigated using power spectral analysis of continuous 5-min ECG recordings. Twelve critically ill patients were included (mean age 54). No adverse effects for the CFT and SWT were noted. The CFT could be performed in 10 patients and showed an abnormal response in 9. The SWT could be performed in 11 patients; results were abnormal in 6. HRV analysis showed decreased HRV in all patients. CFT and HRV responses were correlated with each other, no correlation was found between SWT and CFT or HRV results. The CFT and SWT are feasible and safe in critically ill patients. Cardiovascular dysfunction may be more prevalent in critical illness than peripheral sympathetic dysfunction. Influence of confounders and further validation of these tests needs to be investigated.

Autonomic dysfunction in ICU-acquired weakness: a prospective observational pilot study.

PURPOSE: Intensive care unit-acquired weakness (ICU-AW) is a frequent complication of critical illness. It is unknown if patients with ICU-AW also have autonomic dysfunction, another frequent neurological complication of critical illness. We hypothesized that patients who develop ICU-AW also develop autonomic dysfunction. Furthermore, we hypothesized that patients with ICU-AW are more prone to develop autonomic dysfunction compared to patients without ICU-AW. METHODS: This was an observational cohort study of patients newly admitted to the ICU. Autonomic dysfunction was measured daily using heart rate variability (HRV) to a maximum of 15 days after admission. ICU-AW was diagnosed using the Medical Research Council score. Abnormal HRV was defined using age-matched reference values. The association between ICU-AW and HRV was analyzed using linear mixed effects models. RESULTS: We included 83 patients, 15 (18 %) of whom were diagnosed with ICU-AW. Of 279 HRV measurements, 204 could be analyzed. Abnormal HRV was found in all critically ill patients irrespective of the presence of ICU-AW (ICU-AW 100 % (IQR 71-100) vs. no ICU-AW 100 % (IQR 40-100); p = 0.40). Mechanical ventilation, sedation, norepinephrine, heart rate, and HRV artifacts were identified as confounders for HRV. ICU-AW was not associated with HRV. CONCLUSION: Abnormal HRV is frequent in critically ill patients, both with and without ICU-AW. It is unlikely that patients with ICU-AW are more prone to develop abnormal HRV. However, we found that abnormal HRV may not be an accurate indicator of autonomic dysfunction because of confounders.

Patient satisfaction in neurological second opinions and tertiary referrals.

Although the number of neurological second opinions (SOs) and tertiary referrals (TRs) is increasing, only little is known about expectations and patient satisfaction in this group of patients. Therefore, the purpose of this study was to explore expectations of patients who get a neurological SO or TR and to assess patient satisfaction in these groups of patients. All new patients attending an academic neurological day-care clinic in a 6-month period were investigated. Demographic characteristics, duration of symptoms, expectations and motivation, new diagnoses and treatment consequences were studied, and patient satisfaction with the previous physician and the day-care clinic physician was assessed. Three hundred consecutive patients (183 SOs and 117 TRs) were evaluated. SO patients were younger (47 years vs. 51 years), and their duration of symptoms was longer (24 vs. 13 months) than TR patients. Most patients expected a new diagnosis or treatment (60%). SO patients were equally as satisfied with the day-care clinic consultation as TR patients (overall satisfaction using a VAS-score ranging 0-10: 7.4 vs. 7.5; p = 0.81), and significantly less satisfied with the referring physician (overall satisfaction: 5.6 vs. 7.0; p < 0.001). SO patients, in particular, were more satisfied with the degree of information and emotional support provided by the consulting neurologist as compared to the referring physician. Receiving a new diagnosis and/or treatment advice did not influence satisfaction. A day-care admission for neurological SO and TR leads to an increase of patient satisfaction, irrespective of making a new diagnosis or initiation of a new treatment.